2′-substituted carba-nucleoside analogs for antiviral treatment

Patent metadata

Field	Value
Publication number	US-9481704-B2
Application number	US-201313793557-A
Country	US
Kind code	B2
Filing date	Mar 11, 2013
Priority date	Mar 13, 2012
Publication date	Nov 1, 2016
Grant date	Nov 1, 2016

Abstract

Provided are compounds of Formula I,

as well as pharmaceutical compositions containing compounds of Formula I and methods for treating Orthomyxoviridae virus infections by administering these compounds. The compounds, compositions, and methods provided are particularly useful for the treatment of Human Influenza virus infections.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof;

wherein:
R 1 is halogen, OR a , (C 1 -C 8 )haloalkyl, CN, N 3 , (C 1 -C 8 )alkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl or (C 2 -C 8 )substituted alkynyl,
wherein the substituent is selected from the group consisting of —X, —R b , —OH, ═O, —OR b , —SR b , —S − , —NR b 2 , —N + R b 3 , ═NR b , —CX 3 , —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO 2 , ═N 2 , —N 3 , —NHC(═O)R b , —OC(═O)R b , —NHC(═O)NR b 2 , —S(═O) 2 —, —S(═O) 2 OH, —S(═O) 2 R b , —OS(═O) 2 OR b , —S(═O) 2 NR b 2 , —S(═O)R b , —OP(═O)(OR b ) 2 , —P(═O)(OR b ) 2 , —P(═O)(O − ) 2 , —P(═O)(OH) 2 , —P(O)(OR b )(O − ), —C(═O)R b , —C(═O)X, —C(S)R b , —C(O)OR b , —C(O)O − , —C(S)OR b , —C(O)SR b , —C(S)SR b , —C(O)NR b 2 , —C(S)NR b 2 , —C(═NR b )NR b 2 , where each X is independently a halogen: F, Cl, Br, or I; and each R b is independently H, alkyl, aryl, arylalkyl, a heterocycle, or a protecting group or prodrug moiety;
R 2 is OR a ;
R 3 is halogen or N 3 ;
each R a is independently H, aryl, arylalkyl, or (C 1 -C 8 )alkyl;
R 4 is H, ═O, OR a , N(R a ) 2 , N 3 , CN, S(O) n R a , halogen, or (C 1 -C 8 )haloalkyl;
R 5 is H, OR a , N(R a ) 2 , N 3 , CN, S(O) n R a , halogen, or (C 1 -C 8 )haloalkyl;
each n is 0, 1 or 2;
R 6 is H, aryl, arylalkyl, or

wherein W 1 and W 2 are each, independently, OR a or a group of the Formula Ia:

wherein:
each Y is independently a bond or O;
M2 is 0, 1 or 2;
each R x is H, halogen or OH; and
R 7 is H.

2. The compound of claim 1 , represented by Formula II:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein R 1 is CH 2 OH, CH 2 F, CHF 2 , CH═CH 2 , C≡CH, CN, CH 2 CH═CH 2 , N 3 , CH 3 , or CH 2 CH 3 .

4. The compound of claim 1 , wherein R 2 is OH or O-benzyl.

5. The compound of claim 4 , wherein R 2 is OH.

6. The compound of claim 1 , wherein R 3 is F or N 3 .

7. The compound of claim 6 , wherein R 3 is F.

8. The compound of claim 1 , wherein R 4 is NH 2 and R 5 is H, F, Cl, Br, N 3 , CN, CF 3 , NH 2 , SMe, or SO 2 Me.

9. The compound of claim 1 , wherein R 5 is NH 2 and R 4 is ═O, OH, OMe, Cl, Br, I, NH 2 , NHMe, NHcPr or SMe.

10. The compound of claim 1 , wherein R 4 is selected from the group consisting of H, NH 2 , ═O, NHMe, NHcPr, OH, OMe, Cl, Br, I, SMe, F, N 3 , CN, CF 3 , and SO 2 Me and
R 5 is selected from the group consisting of H, NH 2 , NHMe, NHcPr, OH, OMe, Cl, Br, I, SMe, F, N 3 , CN, CF 3 , and SO 2 Me.

11. The compound of claim 10 , wherein R 5 is H or NH 2 .

12. The compound of claim 10 , wherein R 4 is ═O or NH 2 .

13. The compound of claim 1 , wherein R 6 is H, benzyl, or

wherein W 2 is OH and W 1 is a group of the Formula Ia:

wherein:
Y is O;
M2 is 2; and
each R x is H.

14. The compound of claim 13 , wherein R 6 is H.

15. The compound of claim 1 , wherein R 2 is OH and R 3 is F.

16. The compound of claim 15 , wherein R 4 is NH 2 , H or ═O, R 5 is NH 2 or H and R 6 and R 7 are hydrogen.

17. The compound of claim 1 , wherein R 2 is O-benzyl or OH, R 3 is F, R 4 is SMe, NH 2 or ═O, R 5 is SMe, SO 2 Me, H or NH 2 , R 6 is benzyl or

wherein W 2 is OH and W 1 is a group of the Formula Ia:

wherein:
Y is O;
M2 is 2; and
each R x is H, and R 7 is H.

18. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising:
a therapeutically effective amount of a compound of claim 1 , and
a pharmaceutically acceptable carrier or excipient.

21. The pharmaceutical composition of claim 20 further comprising at least one additional therapeutic agent.

22. The pharmaceutical composition of claim 21 , wherein the at least one additional therapeutic agent is selected from the group consisting of a corticosteroid, an anti-inflammatory signal transduction modulator, a β2-adrenoreceptor agonist bronchodilator, an anticholinergic, a mucolytic agent, hypertonic saline, an agent that inhibits migration of pro-inflammatory cells to the site of infection, and mixtures thereof.

23. The pharmaceutical composition of claim 22 , wherein the at least one additional therapeutic agent is a viral haemagglutinin inhibitor, a viral neuramidase inhibitor, a M2 ion channel inhibitor, a Orthomyxoviridae RNA-dependent RNA polymerase inhibitor or a sialidase.

24. The pharmaceutical composition of claim 22 , wherein the at least one additional therapeutic agent is an interferon, ribavirin, oseltamivir, zanamivir, laninamivir, peramivir, amantadine, rimantadine, CS-8958, favipiravir, AVI-7100, alpha-1 protease inhibitor or DAS181.

25. A method for treating an Orthomyxoviridae infection in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof;

wherein:
R 1 is halogen, OR a , (C 1 -C 8 )haloalkyl, CN, N 3 , (C 1 -C 8 )alkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl or (C 2 -C 8 )substituted alkynyl,
wherein the substituent is selected from the group consisting of —X, —R b , —OH, ═O, —OR b , —SR b , —S − , —NR b 2 , —N + R b 3 , ═NR b , —CX 3 , —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO 2 , ═N 2 , —N 3 , —NHC(═O)R b , —OC(═O)R b , —NHC(═O)NR b 2 , —S(═O) 2 —, —S(═O) 2 OH, —S(═O) 2 R b , —OS(═O) 2 OR b , —S(═O) 2 NR b 2 , —S(═O)R b , —OP(═O)(OR b ) 2 , —P(═O)(OR b ) 2 , —P(═O)(O − ) 2 , —P(═O)(OH) 2 ,

Assignees

• Gilead Sciences Inc

Inventors

• Clarke Michael O'Neil Hanrahan

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• C07H19/23 Primary

  Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22 · CPC title